The mRNA expression profile of cytokines connected to the regulation of melanocyte functioning in vitiligo skin biopsy samples and peripheral blood mononuclear cells (original) (raw)
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New Insights into the Pathogenesis of Vitiligo: Imbalance of Epidermal Cytokines at Sites of Lesions
PIGMENT CELL RESEARCH, 2002
Vitiligo is a skin disease that is caused by selective destruction of melanocytes and is characterized by white spots. Melanocytes and keratinocytes seem to exhibit a functional close relationship, mediated at least in part by keratinocyte-derived cytokines, which seem important for survival and activity of melanocytic cells. We wanted to investigate the hypothesis that in vitiligo the expression of epidermal cytokines may be modified compared with normal skin. In 15 patients with active, non-segmental vitiligo, biopsies were obtained from lesional, perilesional and non-lesional skin; normal skin from five healthy donors was also tested. Tissue sections were tested using immunohistochemistry for the expression of keratinocyte-derived cytokines with stimulating activity, such as granulocyte-monocyte colony stimulating factor (GM-CSF), basic fibroblastic growth factor (bFGF), and stem cell factor (SCF) or with inhibiting activity, such as interleukin 6 (IL-6) and tumour necrosis factor a (TNF-a) on melanocytes.
Journal of Dermatological Science, 2008
Background: Main pathway in human melanocytes through which signal from the melanocortin system reaches the melanogenesis enzymes is cAMP/PKA pathway and it is modulated by Wnt and MAPK pathways. In our previous study we established significant increase of melanocortin receptor expression in unaffected skin of vitiligo patients compared to healthy subjects. Objective: The aim of this study was to assess the gene expression profile of the intracellular signalling pathways linking melanocortin system with enzymes involved in melanogenesis. Methods: Using QRT-PCR method, mRNA expression levels of eight genes related to signal transduction from the melanocortin system to melanogenesis enzymes was measured in lesional and non-lesional skin of vitiligo patients and in the skin of healthy control subjects. Following genes were analyzed in the study: MITF, CREB1, p38, USF1, PIK3CB (PI3K), RPS6KB1, LEF1 and BCL2. Results: The mRNA levels of MITF, LEF1, p38, PIK3CB and RPS6KB1 were decreased in lesional skin of vitiligo patients compared to skin of healthy control subjects. We also found increased expression of USF1 and BCL2 in non-lesional skin of vitiligo patients compared to skin of healthy control subjects. mRNA levels of MITF and BCL2 were decreased in lesional skin of vitiligo patients compared to non-lesional skin of vitiligo patients.
Cytokines: the yin and yang of vitiligo pathogenesis
Expert Review of Clinical Immunology, 2018
Introduction: Dysregulation of melanocyte function is associated with vitiligo, an idiopathic autoimmune hypopigmentary skin disorder, caused by the selective destruction of melanocytes. Cytokines, the key mediators of immune response, which are pivotal in maintaining immune homeostasis, are crucial in vitiligo pathogenesis. Several studies indicate that there is an imbalance between pro-and anti-inflammatory cytokines in the skin and serum of vitiligo patients. Areas covered: In this comprehensive review, we have summarized the correlation of cytokine imbalance and vitiligo pathogenesis, its role in melanocyte biology and its impact on vitiligo treatment. We have integrated various published reports on the levels of major cytokines from skin and serum samples of vitiligo patients. We have also discussed the role of endoplasmic reticulum (ER) and oxidative stress on cytokine imbalance and vice-versa leading to destruction of melanocytes. Expert commentary: The review reflects that dysregulation of cytokines is multi-factorial, ranging from genetic predisposition to altered protein expression relevant to vitiligo pathogenesis. We emphasize that cytokine imbalance in systemic and skin microenvironment plays a crucial role in vitiligo pathogenesis and has promising potential as therapeutic targets for vitiligo.
Predominant role of innate pro-inflammatory cytokines in vitiligo disease
Archives of Dermatological Research, 2019
Vitiligo is a skin disorder with melanocyte destruction and an autoimmune basis. Given the importance of cytokines in autoimmunity, we aimed to find the cytokine profile of innate and adaptive immunity in vitiligo patients, and correlate them with clinical parameters. The serum levels of innate immunity [interleukin(IL)-1α, IL-1β, IL-6, IL-8, IL-12, IL-15 and tumor necrosis factor (TNF)-α] and T helper(Th)1 [IL-2, interferon (IFN)-γ, TNF-β], Th2 (IL-4, IL-5, IL-10, IL-13) and Th17 (IL-17, IL-23) cytokines in 44 vitiligo patients were measured by multiplex cytokine assay and compared with 44 healthy subjects. All innate immunity (p < 0.04), Th1 (p < 0.01), Th2 (p < 0.05) and Th17 (p < 0.001) cytokines were higher in patients than controls. Total summation levels of innate immunity and adaptive immunity cytokines showed a remarkable up-regulation in the patients (p < 0.0001). The ratio of innate immunity to Th1 (p = 0.03), Th2 (p = 0.01) and Th17 (p = 0.03) cytokines was significantly higher in patients vs. controls. We found significant higher ratio of Th1 to Th2 cytokines and TNF-β elevated levels in patients with a family history of autoimmunity (p < 0.05). IL-4 and IL-13 (p < 0.04) levels were lower in patients with amelanotic hair. Increased IL-10 level was observed in patients with stable disease (p = 0.02). In conclusion, the profile of cytokines in patients showed a dominant role of innate immunity pro-inflammatory cytokines in vitiligo, which suggests the potential of targeting these cytokines for vitiligo treatment. While a higher ratio of Th1/Th2 cytokines was observed in the patients, association of decreased Th2 cytokines with disease complications suggests a protective role for Th2 pathway.
Association of IFN- γ : IL-10 Cytokine Ratio with Nonsegmental Vitiligo Pathogenesis
Autoimmune Diseases, 2015
Background and Objectives. Cytokines regulate immune response and inflammation and play a crucial role in depigmentation process of vitiligo. The present study aimed to estimate the serum levels of pro- and anti-inflammatory cytokines, IFN-γand IL-10, and their ratios in nonsegmental vitiligo patients and healthy individuals from India.Methods. Blood samples were collected from 280 subjects and serum IFN-γand IL-10 levels were measured using standard ELISA.Results. Nonsegmental vitiligo patients showed increased levels of IFN-γ(12.4±3.2versus9.9±4.4 pg/mL) and decreased levels of IL-10 (9.3±1.7versus11.5±5 pg/mL) compared to controls. Ratio of IFN-γ : IL-10 differed significantly from patients to controls (p<0.05). IFN-γconcentrations and IFN-γ : IL-10 ratio varied significantly with respect to clinical variants, disease stability, and social habits (smoking and alcohol consumption) and showed a positive correlation with disease duration. Family history of vitiligo was significan...
Immunopathology of Vitiligo: A Review of Literature
Vitiligo is a morbidity characterized by depigmentation of body parts from the loss or reduction of melanocytes. The disease affects an average of 1% of the world population, usually individuals with mean age of 20, affecting both men and women regardless of race. Within existing therapies, there are many treatments being offered, however, improvements upon treatments vary from person to person and cure is rare to obtain. The etiology of vitiligo is still not clear, there are many hypothesis for his cause. Then, this study aimed to review literature regarding the latest immunological mechanisms involved in the onset of vitiligo.
Association of IFN-: IL-10 Cytokine Ratio with Nonsegmental Vitiligo Pathogenesis
2020
Background and Objectives. Cytokines regulate immune response and inflammation and play a crucial role in depigmentation process of vitiligo. The present study aimed to estimate the serum levels of pro-and anti-inflammatory cytokines, IFN-and IL-10, and their ratios in nonsegmental vitiligo patients and healthy individuals from India. Methods. Blood samples were collected from 280 subjects and serum IFN-and IL-10 levels were measured using standard ELISA. Results. Nonsegmental vitiligo patients showed increased levels of IFN-(12.4 ± 3.2 versus 9.9 ± 4.4 pg/mL) and decreased levels of IL-10 (9.3 ± 1.7 versus 11.5 ± 5 pg/mL) compared to controls. Ratio of IFN-: IL-10 differed significantly from patients to controls ( < 0.05). IFN-concentrations and IFN-: IL-10 ratio varied significantly with respect to clinical variants, disease stability, and social habits (smoking and alcohol consumption) and showed a positive correlation with disease duration. Family history of vitiligo was sign...
Histology and histopathology, 2009
Vitiligo is a skin disorder characterized by loss of functional melanocytes. Keratinocytes contribute to melanocyte homeostasis, and keratinocyte alteration may play a role in melanocyte dysfunction in vitiligo. In particular, the release of melanogenic mediators and the level of functioning keratinocytes may affect melanocyte dysfunction in vitiligo epidermis. Keratinocyte-derived mediators involved in pigmentation, analysed by in situ hybridization, and epidermal apoptosis, detected by TUNEL assay and electron microscopy, were evaluated in lesional and perilesional skin biopsies from 15 patients with active vitiligo and in 5 control subjects. Among the melanogenic mediators, stem cell factor (SCF) and endothelin-1 (ET-1) mRNA were significantly reduced in lesional as compared to perilesional epidermis, whereas no difference was observed in mRNA of basic fibroblastic growth factor (bFGF) and granulocyte-monocyte colony stimulating factor (GM-CSF). The expression of mRNA for tumor n...
Investigation of the Role of Interleukin 6 in Vitiligo Pathogenesis
Immunological Investigations, 2020
Interleukin-6 (IL6) is involved in pathogenesis of several autoimmune disorders including vitiligo. Hence, we aimed to investigate the association of IL6 −174 G/C and −572 G/C polymorphisms and its transcript levels with vitiligo; to evaluate the effect of IL-6 on normal human melanocyte (NHM) viability and expression of IL6R, MITF and TYR. IL6-174 G/C and −572 G/C polymorphisms were genotyped by ARMS-PCR and PCR-RFLP respectively in 343 controls and 322 vitiligo patients. IL6 transcript levels were estimated from PBMCs (96 controls and 77 patients) and skin samples (15 controls and 15 patients) by qPCR. NHM viability was assessed by MTT; IL6R, MITF and TYR transcript and protein levels were monitored by qPCR and ICC respectively. Genetic analyses revealed no association of IL6 −174 G/C polymorphism (p> .05) with vitiligo. Analysis of IL6 −572 G/C revealed reduced risk of vitiligo in individuals with GC/CC genotypes compared to GG genotype (p = .010). IL6 expression was significantly increased (p = .0197) in PBMCs of patients. Further, IL6 expression was significantly higher in non-lesional skin compared to controls (p = .009). In-vitro NHM viability was decreased upon IL-6 exposure (10-50 ng/ml; p< .05), with significantly increased IL6R transcript (p = .042) and protein levels (p = .003) however, MITF transcript (p = .0003) and protein levels (p = .016), and TYR transcript levels (p = .001) were significantly decreased. The results suggest that IL6 −572 G/C polymorphism might be associated with vitiligo susceptibility in Gujarat population. Moreover, increased IL6 expression in vitiligo patients and its effect on NHM suggest a potential role in melanocyte biology. Conclusion: The results suggest that IL6 − 572 G/C polymorphism might be associated with vitiligo susceptibility in Gujarat population. Moreover, increased IL6 expression in vitiligo patients and its effect on NHM suggest a potential role in melanocyte biology.
Association analysis of class II cytokine and receptor genes in vitiligo patients
Human Immunology, 2016
The loss of melanocytes in vitiligo is mainly attributed to defective autoimmune mechanisms and lately autoinflammatory mediators have become more emphasized. Among these, a number of class II cytokines and their receptors have displayed altered expression patterns in vitiligo. Thus, we selected 30 SNPs from the regions of respective genes to be genotyped in Estonian case-control sample (109 and 238 individuals, respectively). For more precise analyses, patients were divided into subgroups based on vitiligo progression activity, age of onset, sex, occurrence of vitiligo among relatives, extent of depigmented areas, appearance of Köbner's phenomenon, existence of halo nevi, occurrence of spontaneous repigmentation, and amount of thyroid peroxidase antibodies. No associations appeared in whole vitiligo group. In subgroups, several allelic and haplotype associations were found. The strongest involved SNPs rs12301088 (near IL26 gene), that was associated with familial vitiligo and existence of halo nevi, and rs2257167 (IFNAR1 gene), that was associated with female vitiligo. Additionally, haplotypes consisting of rs12301088 and rs12321603 alleles (IL26-IL22 genes), that were associated with familial vitiligo and existence of halo nevi. In conclusion, several genetic associations with vitiligo subphenotypes were revealed and functional explanations to these remain to be determined in respective studies.